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A regression-based analysis of ribosome-profiling data reveals a conserved complexity to mammalian translation

ABSTRACT: A fundamental goal of genomics is to identify the complete set of expressed proteins. Automated annotation strategies rely on assumptions about protein-coding sequences (CDSs), e.g., they are conserved, do not overlap, and exceed a minimum length. However, an increasing number of newly discovered proteins violate these rules. Here we present an experimental and analytical framework, based on ribosome profiling and linear regression, for systematic identification and quantification of translation. Application of this approach to lipopolysaccharide-stimulated mouse dendritic cells and HCMV-infected human fibroblasts identifies thousands of novel CDSs, including micropeptides and variants of known proteins, that bear the hallmarks of canonical translation and exhibit comparable translation levels and dynamics to annotated CDSs. Remarkably, many translation events are identified in both mouse and human cells even when the peptide sequence is not conserved. Our work thus reveals an unexpected complexity to mammalian translation suited to provide both conserved regulatory or protein-based functions.

ORGANISM(S): Mus musculus

PROVIDER: GSE74139 | GEO | 2015/12/03

SECONDARY ACCESSION(S): PRJNA299160

REPOSITORIES: GEO

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A regression-based analysis of ribosome-profiling data reveals a conserved complexity to mammalian translation

Project description:A fundamental goal of genomics is to identify the complete set of expressed proteins. Automated annotation strategies rely on assumptions about protein-coding sequences (CDSs), e.g., they are conserved, do not overlap, and exceed a minimum length. However, an increasing number of newly discovered proteins violate these rules. Here we present an experimental and analytical framework, based on ribosome profiling and linear regression, for systematic identification and quantification of translation. Application of this approach to lipopolysaccharide-stimulated mouse dendritic cells and HCMV-infected human fibroblasts identifies thousands of novel CDSs, including micropeptides and variants of known proteins, that bear the hallmarks of canonical translation and exhibit comparable translation levels and dynamics to annotated CDSs. Remarkably, many translation events are identified in both mouse and human cells even when the peptide sequence is not conserved. Our work thus reveals an unexpected complexity to mammalian translation suited to provide both conserved regulatory or protein-based functions. 37 ribosome footprint samples from mouse BMDCs across a time course of LPS stimulation and in the presence or absence of translation inhibitors cycloheximide, harringtonine, or lactimidomycin. A mock (non-LPS stimulated) time course is also included, collected in the presence of cycloheximide. Two replicates are available for the LPS timecourse under CHX treatment.

2015-12-03 | E-GEOD-74139 | biostudies-arrayexpress

A regression-based analysis of ribosome-profiling data reveals a conserved complexity to mammalian translation

Project description:Alexander P. Fields, Edwin H. Rodriguez, Marko Jovanovic, Noam Stern-Ginossar, Brian J. Haas, Philipp Mertins, Raktima Raychowdhury, Nir Hacohen, Steven A. Carr, Nicholas T. Ingolia, Aviv Regev, and Jonathan S. Weissman.Molecular Cell 2015. A fundamental goal of genomics is to identify the complete set of expressed proteins. Automated annotation strategies rely on assumptions about protein-coding sequences (CDSs), e.g., they are conserved, do not overlap, and exceed a minimum length. However, an increasing number of newly discovered proteins violate these rules. Here we present an experimental and analytical framework, based on ribosome profiling and linear regression, for systematic identification and quantification of translation. Application of this approach to lipopolysaccharide-stimulated mouse dendritic cells and HCMV-infected human fibroblasts identifies thousands of novel CDSs, including micropeptides and variants of known proteins, that bear the hallmarks of canonical translation and exhibit comparable translation levels and dynamics to annotated CDSs. Remarkably, many translation events are identified in both mouse and human cells even when the peptide sequence is not conserved. Our work thus reveals an unexpected complexity to mammalian translation suited to provide both conserved regulatory or protein-based functions.

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Ribosome profiling of dhh1∆ yeast

Project description:The impact of RNA structures in coding sequences (CDS) within mRNAs is poorly understood. Here  we identify a novel and highly conserved mechanism of translational control involving RNA structures within coding sequences and the DEAD-box helicase Dhh1. Using yeast genetics and  genome-wide ribosome profiling analyses we show that this mechanism, initially derived from studies  of the Brome Mosaic virus RNA genome, extends to yeast and human mRNAs highly enriched in  membrane and secreted proteins. All Dhh1-dependent mRNAs, viral and cellular, share key common  features. First, they contain long and highly structured CDSs, including a region located around 42 to  120 nucleotides after the translation initiation site, second, they are directly bound by Dhh1 with a  specific binding distribution and third, complementary experimental approaches suggest that they are  activated by Dhh1 at the translation initiation step. Our results show that ribosome translocation is not the only unwinding force of CDS and uncover a conserved layer of translational control that involve  RNA helicases and RNA folding within CDS providing novel opportunities for regulation of  membrane and secretome proteins.

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A novel translational control mechanism involving RNA structures within coding sequences

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Ribosome Profiling of Mouse Embryonic Stem Cells Reveals the Complexity of Mammalian Proteomes

Project description:The ability to sequence genomes has far outstripped approaches for deciphering the information they encode. Here we present a suite of techniques, based on ribosome profiling (the deep-sequencing of ribosome-protected mRNA fragments), to provide genome-wide maps of protein synthesis as well as a pulse-chase strategy for determining rates of translation elongation. We exploit the propensity of harringtonine to cause ribosomes to accumulate at sites of translation initiation together with a machine learning algorithm to define protein products systematically. Analysis of translation in mouse embryonic stem cells reveals thousands of strong pause sites and novel translation products. These include amino-terminal extensions and truncations and upstream open reading frames with regulatory potential, initiated at both AUG and non-AUG codons, whose translation changes after differentiation. We also define a new class of short, polycistronic ribosome-associated coding RNAs (sprcRNAs) that encode small proteins. Our studies reveal an unanticipated complexity to mammalian proteomes. Examination of translation in mouse embryonic stem cells and during differentiation into embryoid bodies

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The RSC complex remodels nucleosomes in transcribed coding sequences and promotes transcription in Saccharomyces cerevisiae

Project description:RSC (Remodels the Structure of Chromatin) is a conserved ATP-dependent chromatin remodeling complex that regulates many biological processes, including transcription by RNA polymerase II (Pol II). We report that not only RSC binds to nucleosomes in coding sequences (CDSs) but also remodels them to promote transcription. RSC MNase ChIP-seq data revealed that RSC-protected fragments were very heterogenous (~80 bp to 180 bp) compared to the sharper profile displayed by the MNase inputs (140 bp to 160 bp), supporting the idea that RSC activity promotes accessibility of nucleosomal DNA. Importantly, RSC binding to +1 nucleosomes and CDSs, but not with -1 nucleosomes, strongly correlated with Pol II occupancies suggesting that the RSC enrichment in CDSs is important for efficient transcription. This is further supported by a similar heterogenous distribution of Pol II-protected fragments. As such, the genes harboring high-levels of RSC in their CDSs were the most strongly affected by ablating RSC function. Altogether, this study provides a mechanism by which RSC-mediated remodeling aids in RNA Pol II traversal though coding sequence nucleosomes in vivo.

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